We have described two dsRNA viruses (L A and L BC) and two ssRNA replicons (20S RNA and 23S RNA) in the yeast Saccharomyces cerevisiae. M dsRNA is a satellite of L A encoding the killer toxin. We discovered 7 chromosomal genes, SKI1, 2, 3, 4, 6, 7, and 8, by their ability to prevent these replicons from causing pathogenicity to yeast cells. These four RNA replicons all make uncapped mRNAs and lack a 3' poly(A)structure. SKI1 is an exoribonuclease specific for uncapped mRNAs, while we showed that the SKI2, SKI3, SKI6, SKI7 and SKI8 gene products block the translation of non-poly(A) mRNAs. We showed that Ski2p is an RNA helicase, Ski6p has homology to a tRNA - processing RNAse, and Ski7p is similar to translation factor EF1*. We showed that mutations in 20 chromosomal genes resulting in loss of M dsRNA are deficient in 60S ribosomal subunits. These mutations are suppressed by ski mutations without restoration of the 60S subunit deficiency. We proposed that SKI2, SKI3 and SKI8 block translation of non-poly(A) mRNA by an effect on ribosome biogenesis affecting the interaction of 60S subunits with the 3' poly(A) structure of the mRNA. We have now cloned MAK21 and found it similar to a human CAATT box binding protein known to regulate Hsp70 transcription. While yeast Mak21p does not regulate the homologous yeast Hsp70, it is essential for growth because it is required specifically for 60S ribosomal subunit biogenesis. Electroporation of model mRNAs shows that mak21-1 mutants are specifically impaired in translation of mRNAs lacking the 5' cap or 3' poly(A) structures, explaining their poor translation of viral mRNAs which also lack these structures.